Gareau Alison, Hirsch Gregory M, Lee Tim D G, Nashan Bjorn
Department of Surgery, Atlantic Centre for Transplantation Research, Microbiology and Immunology and Pathology, Dalhousie University, Halifax, NS, Canada.
Transplantation. 2009 Aug 27;88(4):470-7. doi: 10.1097/TP.0b013e3181b076cc.
The aim of this study was to determine the role of alloantibody in the development of cardiac allograft vasculopathy (AV). AV is the main pathologic indicator of chronic cardiac graft rejection resulting in graft loss at 10 years posttransplant. In AV, a neointimal lesion forms resulting in luminal occlusion and damage to the transplanted organ. AV is T-cell mediated, but the role played by B cells and antibody in AV development has been controversial. No studies have been conducted in the presence of a clinically relevant immunosuppressant. In our study, we use cyclosporin A, a calcineurin inhibitor.
Two models of B-cell deficiency were used as recipients of a C3H/HeJ abdominal aortic graft; grafts were harvested at 8 weeks. T- and B-cell immunodeficient mice (RAG1-/-) received passively transferred anti-C3H antibody, raised in B6 mice. Cyclosporin A was administered daily to both control and experimental groups. Alpha-actin staining was used to identify myofibroblasts in the neointima.
Lesions in B-cell-deficient B6 mice were not significantly different in size from those of control mice. Lesions in both B-cell-deficient and wild-type mice showed similar levels of alpha-actin positivity. Passive transfer of antibody to RAG1-/- mice resulted in small, alpha-actin-positive lesions.
B cells are not required for the development of AV, but the presence of an alloantibody can contribute to AV. We hypothesize that the alloantibody mediates AV by initiating complement-mediated killing of smooth muscle cells, based on an in vitro work. Of interest, we found that the neointimal lesions of B-cell-deficient mice and mice that received antibody showed the presence of alpha-actin in myofibroblasts.
本研究的目的是确定同种异体抗体在心脏移植血管病变（AV）发展中的作用。AV是慢性心脏移植排斥反应的主要病理指标，可导致移植后10年移植器官丧失。在AV中，形成新内膜病变，导致管腔闭塞和移植器官受损。AV是由T细胞介导的，但B细胞和抗体在AV发展中所起的作用一直存在争议。在存在临床相关免疫抑制剂的情况下尚未进行过研究。在我们的研究中，我们使用钙调神经磷酸酶抑制剂环孢素A。
将两种B细胞缺陷模型用作C3H/HeJ腹主动脉移植物的受体；在8周时采集移植物。T细胞和B细胞免疫缺陷小鼠（RAG1-/-）接受了在B6小鼠中产生的被动转移抗C3H抗体。对照组和实验组均每日给予环孢素A。使用α-肌动蛋白染色来鉴定新内膜中的肌成纤维细胞。
B细胞缺陷的B6小鼠中的病变大小与对照小鼠的病变大小无显著差异。B细胞缺陷小鼠和野生型小鼠中的病变均显示出相似水平的α-肌动蛋白阳性。将抗体被动转移至RAG1-/-小鼠导致出现小的、α-肌动蛋白阳性病变。
AV的发展不需要B细胞，但同种异体抗体的存在可促进AV。基于一项体外研究，我们推测同种异体抗体通过启动补体介导的平滑肌细胞杀伤来介导AV。有趣的是，我们发现B细胞缺陷小鼠和接受抗体的小鼠的新内膜病变在肌成纤维细胞中存在α-肌动蛋白。
